The fibroblast growth factor receptor (FGFR) family is composed of four members (FGFR1, FGFR2, FGFR3, and FGFR4), which is a kinase belonging to the receptor tyrosine kinase family, and the binding of FGF leads to FGFR dimerization, followed by autologous phosphorylation of receptors and activation of downstream signaling pathways. Activation of receptors is sufficient to regenerate and activate specific downstream signaling partners involved in the regulation of diverse processes such as cell growth, cell metabolism, and cell survival. Therefore, the FGF/FGFR signaling pathway has multiple effects in many critical cellular biological processes such as tumor cell proliferation, migration, infiltration, and angiogenesis. The four members of the FGFR family differ from each other in terms of their ligand affinity and tissue distribution. The genomic structure of the FGFR-4 gene contains 18 exons.
Human FGF19 gene is located at 11q13.1, the specific binding of FGFR4 to its ligand FGF19 inhibits cell apoptosis and NF-kB signaling, and up-regulates expression of genes involved in cell proliferation; activation of FGFR4 may lead to a decrease in Ikkβ activity in TNF-α-treated cells, along with the reduction of NF-kB distribution in cells, and attenuates the cell apoptotic effect. Four FGFR genes are expressed in human liver, but mature hepatocyte only expresses FGFR4 in large amounts. The binding of FGFR4 to its ligand can also regulate the metabolism of bile acid. The balance of the conversion of cholesterol to bile acid in the body is closely related to various normal physiological functions of the body. Damage of this balance can cause various diseases, for example fatty liver and cardiovascular and cerebrovascular diseases such as arteriosclerosis. Therefore, the interaction between FGFR4 and FGF19 has become a new target for cholesterol-lowering drugs in the treatment of diseases such as hyperlipidemia.
In recent years, more and more evidence indicates that there are gene amplification mutations of FGFR1, FGFR2, FGFR3 and FGFR4 in various types of cancer. A large amount of evidence indicates that FGFR1 has gene mutations in breast cancer, non-small cell lung cancer and glioblastoma, has fusion protein formation caused by gene transposition in acute myeloid leukemia, and has over-expression in pancreatic cancer, bladder cancer, prostate cancer, and esophageal cancer; FGFR2 has gene mutations and amplification in gastric cancer, breast cancer and uterine cancer, and has over-expression in prostate cancer, esophageal cancer, ovarian cancer, pancreatic cancer, brain tumor, and colorectal cancer; FGFR3 has gene mutations in multiple myeloma and bladder cancer, and has over-expression in ovarian cancer, non-small cell lung cancer, and hepatocellular carcinoma; FGFR4 has gene mutations and over-expression in lung cancer, ovarian cancer, prostate cancer, hepatocellular carcinoma and cholangiocarcinoma etc., and also has over-expression in thyroid cancer, ovarian cancer, etc. (French et al. 2012 PLos ONE 7(5):e367313; Sia et al. 2013 Gastroejterology 144:829-840).
A series of patents about FGFR inhibitor have been published, however, there are fewer patent disclosures on selective inhibition of FGFR4, and inhibitors selective for FGFR4 have less toxicity than FGFR inhibitors (Brown, A P et al (2005), Toxocol. Pathol., 449-455). FGFR4 inhibitors currently in clinical include FGF-401 (Novartis, clinical phase II), BLU-554 (Blueprint, clinical phase I) and H3B6527 (Eisai, clinical phase I). Patents for selective inhibition of FGFR4 include WO2015059668, WO2015057938, and WO2015057963, etc. Currently, research on FGFR4 inhibitors against tumors such as hepatocellular carcinoma is insufficient, and it is still necessary to study and develop new FGFR4 inhibitors.